CF is an inherited disorder which occurs in 1/2000 births. The gene responsible for this disease produces the Cystic Fibrosis Transmembrane Regulator (CFTR) protein. This protein is thought to regulate passage of chloride ions through cell membranes. Different mutations in the CFTR gene may potentially lead to different phenotypes, as demonstrated by the variability in organ involvement and severity of CF. A sweat chloride value greater than 70 mEq/L has been the gold standard for diagnosis in CF. "Borderline" (40-70 mEq/L) values are often associated with mild CF symptoms but not tied to a CF diagnosis. Many patients with a mild pulmonary phenotype similar to that observed in this borderline population are adults who have never had sweat tests performed. Based on the hypotheses that a mild, pancreatic sufficient, chronic obstructive pulmonary disease phenotype with "borderline" sweat chloride is linked to mutation(s) in the CFTR gene, the applicant will characterize the phenotypes of 1) a large population of borderlines and 2) subjects with chronic respiratory disorders from several well defined longitudinal study populations. The CFTR genotypes will then be characterized in these populations by ASO, SSCP and DNA sequencing, and based on preliminary data that suggests unique CFTR genotypes are presented in these populations, develop a molecular genetic screening panel for appropriate mutations. The significance of associating chronic debilitating pulmonary disorders other than CF (such as chronic bronchitis and chronic obstructive pulmonary disease) with CFTR gene abnormalIties would improve insight into the pathophysiology and potential therapy of those disorders.